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G-quadruplex DNA reprograms the photochemistry of CX-5461 toward radical-driven anticancer activity
Jakub Trojnar1, Maria V Cottini2, Marta Dudek1
1Faculty of Chemistry, Institute of Advanced Materials, Wrocław University of Science and Technology, Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland.
Abstract:
CX-5461 (pidnarulex) is the most clinically advanced small-molecule ligand associated with G-quadruplex (G4) targeting and shows activity in DNA repair-deficient tumors, yet its clinical use is associated with dose-limiting phototoxicity. Here, we repurpose this intrinsic photoreactivity to investigate CX-5461 as a G4-associated, light-activated antitumor scaffold. In solution, CX-5461 produces both Type I and Type II reactive oxygen species (ROS), whereas complexation with G4 DNA markedly decreases detectable singlet oxygen (1O2) formation and favors radical-associated Type I oxidation. This G4-modulated photochemical shift drives oxidative remodeling and destabilization of G4-containing DNA. In cancer cells, photoactivation enhances cytotoxicity by up to two orders of magnitude relative to the dark state and is accompanied by elevated intracellular ROS, increased 8-oxoG formation, γ-H2AX accumulation, and changes in BG4-detected nuclear G4 structures. In vivo, light-activated CX-5461 suppresses tumor growth and extends survival in immunocompetent syngeneic models, eliciting hallmarks consistent with immunogenic genome stress. Collectively, these findings reposition CX-5461 as a clinically relevant scaffold for G4-associated photogenomic cancer therapy, while supporting a model in which broader oxidative DNA damage may also contribute to the biological response.
Insights
CX-5461, a G-quadruplex (G4) targeting drug, can be repurposed as a light-activated cancer therapy. Photoactivation significantly enhances its antitumor effects by increasing DNA damage and triggering an immune response.
Area of Science:
- Oncology
- Photochemistry
- Molecular Biology
Background:
- CX-5461 is a G-quadruplex (G4) targeting small molecule with demonstrated activity in DNA repair-deficient tumors.
- Clinical use of CX-5461 is limited by dose-limiting phototoxicity.
Purpose of the Study:
- To investigate CX-5461 as a G-quadruplex-associated, light-activated antitumor scaffold by repurposing its phototoxicity.
- To elucidate the photochemical properties of CX-5461 in solution and when complexed with G4 DNA.
Main Methods:
- Investigated CX-5461's photochemical properties (ROS production) in solution and G4 DNA complexes.
- Assessed the cytotoxicity of photoactivated CX-5461 in cancer cells, measuring intracellular ROS, 8-oxoG, and γ-H2AX.
- Evaluated the in vivo efficacy of light-activated CX-5461 in immunocompetent syngeneic tumor models.
Main Results:
- CX-5461 produces both Type I and Type II reactive oxygen species (ROS) in solution.
- G4 DNA complexation shifts CX-5461's photochemistry towards Type I oxidation, destabilizing G4 DNA.
- Photoactivated CX-5461 demonstrated a two-log enhancement in cytotoxicity, increased DNA damage markers, and altered nuclear G4 structures in cancer cells.
- In vivo, light-activated CX-5461 suppressed tumor growth and extended survival, inducing immunogenic genome stress.
Conclusions:
- CX-5461 can be repositioned as a clinically relevant scaffold for G-quadruplex-associated photogenomic cancer therapy.
- The findings support a model where broader oxidative DNA damage contributes to the biological response of light-activated CX-5461.
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